Esophageal squamous cell carcinoma (ESCC) is responsible for approximately one-sixth of all cancer-related deaths worldwide. This malignancy is due to several environmental, dietary and genetic factors. Since esophageal cancer has often metastasized at the time of diagnosis, current treatment modalities offer poor survival and cure rates. There is a need for improved imaging diagnostics to screen for subtle changes that precede the onset of ESCC. Since ESCC originates from the squamous cells that line the inner surface of the esophagus, the imaging of altered protein expression (molecular biomarkers) at these surfaces could be used to monitor disease progression. However, due to the variability in molecular expression patterns between patients, and within a single patient over time, accurate disease diagnosis would benefit from the ability to image a large number of molecular targets. Therefore, we are developing an in vivo imaging device to image surface-enhanced Raman scattering (SERS) nanoparticles that are capable of being highly multiplexed to target a large number of protein biomarkers. This feasibility study will develop and demonstrate these technologies in a well-established rat model of ESCC. This two-year exploratory study will develop technologies, and provide evidence of feasibility, to enable future studies to visualize alterations in molecular expression that occur during the progression of ESCC in a rat model, as well as to investigate the molecular changes that occur in response to therapy. In the future, we will work with collaborators to develop SERS particles to target a variety of biomarkers that are relevant for this cancer model, as well as in humans. Our ultimate goal is to better understand the molecular transformations associated with cancer progression in this rat model as well as in human esophageal cancers, thus enabling accurate early detection, assessment of therapy response, and personalized treatments. Efforts are being made, including toxicity studies, to secure FDA approval for the translation of these imaging devices and nanoparticles into humans.